1. Field of the Invention
The present invention relates to a recombinant vaccinia virus incorporated with a gene coding glutamic acid decarboxylase (hereinafter “GAD”) and a vaccine for preventing type 1 diabetes mellitus comprising the same. More particularly, this invention relates to a recombinant vaccinia virus containing a gene coding GAD which is known as pancreatic β cell target autoantigen. The GAD expressed from the recombinant virus suppresses the autoreactive T cell, and induces immunological tolerance, thus effectively prevents or delays the development of type 1 diabetes mellitus.
2. Description of the Related Art
Generally, diabetes mellitus is one of the common metabolic disorders resulting from shortage of insulin, and classified into type 1 diabetes mellitus and type 2 diabetes mellitus according to the effect of insulin injection therapy. Among them, the symptoms of the type 1 diabetes mellitus is relieved by insulin therapy, and the diabetes is generally called as “insulin-dependent diabetes mellitus(IDDM)”. The type 1 diabetes mellitus results from the pancreatic β cell destruction due to β cell-specific autoimmunity mediated by the antigen-specific T cells in humans and nonobese diabetic (NOD) mice, and “insulitis” is the major symptom of the disease.
Identification of the primary target β cell antigens in type 1 diabetes mellitus is critical for understanding the initiation of 3 cell-specific autoimmunity by antigen-specific T cells. Many β cell target autoantigens have been identified in humans, nonobese diabetic (NOD) mice and Biobreeding rats, and among these, glutamic acid decarboxylase (GAD) is the strongest candidate in both humans and NOD mice (Tisch, R. et al., Nature 366, 72-75, 1993). In support of this view, we recently found that the β cell-specific suppression of GAD expression results in the prevention of autoimmune diabetes in NOD mice (J. W. Yoon et al., Science 284, 1183-1187, 1999), indicating that GAD expression is essential for the disease induction.
Thus, various methods of suppressing the T cell mediated immune response against pancreatic β cells and thereby inhibiting β cell destruction were developed to prevent or delay insulitis and diabetes. For example, it has been reported that immunization of NOD mice with purified GAD protein (Elliot, J. F., et al., Diabetes 43, 1494-1499,1994) or oral administration of the GAD by feeding with GAD-expressing plants (Ma, S. W., et al., Nature Med. 3. 793-796, 1997) can tolerize the T cell mediated immune response against pancreatic β cells. However, drawbacks to the former method are the difficulty in producing large amount of GAD protein in bacteria due to its insolubility, and the great expense required for the labor-intensive production of large amounts of GAD protein in baculovirus or mammalian cells. Feeding with GAD producing plants also has drawbacks, due to the limited concentration of GAD in the plant and the requirement for long-term feeding.